HAEM5:Myeloid proliferations associated with Down syndrome: Difference between revisions

Transient abnormal myelopoiesis occurs exclusively in patients with Down syndrome (constitutional trisomy 21), and affects approximately 4% to 10% of neonates. TAM manifests in the neonatal period, and is characterized by circulating megakaryoblasts with varied degrees of multisystem organ involvement. The median age of presentation is 3 to 7 days, though patients may be diagnosed at up to 2 months of life. The most common clinical manifestations include hepatomegaly (60%), splenomegaly (35%–40%), jaundice (15%), pericardial effusion (15%), pleural effusion (10%–15%), ascites (10%), respiratory distress (10%), and bleeding diathesis (10%). Less common features include hepatic fibrosis, hydrops fetalis, and renal failure. Characteristic hematologic findings include leukocytosis (WBC > 100K/μL in 20%–30%), thrombocytopenia (40%), and increased numbers of circulating blasts. Approximately 10% to 25% of patients are asymptomatic; thus, the diagnosis may be established as an incidental finding during laboratory assessment for some other cause. Occasionally, the finding of TAM may even be the first indication that a patient has trisomy 21.

Approximately 20% of patients with TAM develop AMKL within the first 4 years of life and this may be preceded by a myelodysplastic-like syndrome. The World Health Organization classification category “myeloid leukemia associated with DS” (DS-AMKL) encompasses both myelodysplastic and leukemic manifestations regardless of blast percentage. The median age of onset is 2 years, younger than that seen in non–DS-AMKL. Patients typically manifest with low WBC count, cytopenia, organomegaly, progressive marrow fibrosis, and clonal cytogenetic abnormalities, e.g., trisomy 8. Blasts in DS-AMKL are morphologically and immunophenotypically similar to those seen in TAM. Patients with DS-AMKL have a favorable prognosis with 80% 3-year overall survival. This response rate is, in part, attributed to enhanced chemosensitivity of megakaryoblasts to cytarabine. The cytidine deaminase gene functions in cytarabine catabolism, and its transcription is diminished in DS, which may lead to diminished intracellular drug metabolism and consequent increased drug efficacy<ref name=":0" /><ref name=":1" /><ref name=":2" /><ref name=":3" /><ref name=":4" />.

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==Sites of Involvement==

Phenotypically, blasts commonly express stem cell (variable CD34, CD117), myeloid (CD13, CD33), nonlineage (CD4, CD7, CD56), and megakaryoblastic/megakaryocytic (CD61, CD41, CD42) antigens<ref name=":4" />.

The blasts in TAM have a characteristic megakaryoblastic immunophenotype. In most cases, the leukemic blasts are positive for CD34, KIT (CD117), CD13, CD33, HLA-DR, CD4 (dim), CD41, CD42, CD110 (TPOR), IL3R, CD36, CD61, and CD71, often with expression of CD7 and CD56. The blasts are negative for MPO, CD15, CD14, CD11a, and glycophorin A. IHC with CD41, CD42b, and CD 61 may be particularly useful for identifying blasts of megakaryocytic lineage in BM biopsies<ref name=":0" />.

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==Chromosomal Rearrangements (Gene Fusions)==

not applicable

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* Individual Region Genomic Gain/Loss/LOH

* Characteristic Chromosomal Patterns

Transient abnormal myelopoiesis is a preleukemic disorder that occurs only in neonates with constitutional trisomy 21. Transient abnormal myelopoiesis typically presents in the first week of life with leukocytosis, thrombocytopenia, hepatomegaly, and circulating megakaryoblasts, the latter of which contain an acquired ''GATA1'' mutation. Although TAM can be fatal in 10% of patients, it most often resolves spontaneously, but is believed to persist in a “quiescent” state. By 5 years of age, 20% of patients progress to AMKL following an intervening remission and/or a preceding myelodysplastic-like syndrome. Down syndrome–AMKL has a favorable prognosis with enhanced chemotherapeutic responsiveness to cytarabine.

Given the risk of progression to DS-AMKL, some advocate that all neonates with DS undergo routine screening for TAM with manual peripheral blood smear review and ''GATA1'' mutation analysis. With detection of a ''GATA1'' mutation, clinical assessment and routine laboratory screening is then suggested periodically throughout early childhood<ref name=":0" /><ref name=":4" />.

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==Individual Region Genomic Gain / Loss / LOH==

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not applicable

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==Characteristic Chromosomal Patterns==

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Constitutional trisomy 21 or mosaic constitutional trisomy 21

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==Gene Mutations (SNV / INDEL)==

Not applicable

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==Epigenomic Alterations==

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In addition to trisomy 21, acquired ''GATA1'' mutations are present in blast cells of TAM [1].

TAM is the result of a multistep process in which trisomy 21 is the “initiating” event in disease pathogenesis. Trisomy 21 creates an environment, in utero, in which hematopoietic progenitor cells within fetal liver are primed for acquisition of either single or multiple somatic ''GATA1'' mutations that reflect a “secondary hit,” thereby promoting hematopoietic dysregulation and emergence of TAM. With birth, hematopoiesis naturally transitions from fetal liver to bone marrow and the ''GATA1'' megakaryoblastic clone becomes quiescent. However, this clone persists over time and undergoes other somatic mutations and epigenetic events ultimately lead to the impaired megakaryocytic differentiation and uncontrolled proliferation characteristic of DS-AMKL<ref name=":1" /><ref name=":2" /><ref name=":3" /><ref name=":4" />.

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==Genetic Diagnostic Testing Methods==